Inhibition of Endometrial Cancer by n-3 Polyunsaturated Fatty Acids in Preclinical Models

Abstract

Although preclinical and epidemiologic studies have shown the importance of n-3 polyunsaturated fatty acids (PUFA) in the prevention of hormone-responsive cancers such as breast cancer, evidence of the association between n-3 PUFAs and endometrial cancer risk is limited and no previous study has examined the effect of n-3 PUFAs on endometrial cancer in cellular and animal models. In this study, we demonstrated that docosahexenoic acid (DHA) dose-and time-dependently inhibited endometrial cancer cell proliferation, colony formation, and migration and promoted apoptosis. Dietary n-3 PUFAs efficiently prevented endometrial cancer cell growth in xenograft models. Moreover, ectopic expression of fat-1, a desaturase, catalyzed the conversion of n-6 to n-3 PUFAs and produced n-3 PUFAs endogenously, also suppressed endometrial tumor cell growth and migration, and potentiated apoptosis in endometrial cancer cell lines. Interestingly, implanted endometrial cancer cells were unable to grow in fat-1 transgenic SCID mice. Further study revealed that mTOR signaling, which plays an essential role in cell proliferation and endometrial tumorigenesis, is a target of n-3 PUFAs. Exogenous or endogenous n-3 PUFAs efficiently suppressed both mTOR complex 1 (mTORC1) and mTORC2 in vitro and in vivo. Moreover, both dietary n-3 PUFAs and transgenic expression of fat-1 in mice effectively repressed mTORC1/2 signaling and endometrial growth elicited by unopposed estrogen. Taken together, our findings provide comprehensive preclinical evidences that n-3 PUFAs efficiently prevent endometrial cancer and establish mTORC1/2 as a target of n-3 PUFAs. Cancer Prev Res; 7(8); 824-34. Ó2014 AACR.

An Ω-3 fatty acid desaturase-expressing gene attenuates prostate cancer proliferation by cell cycle regulation

“…The results demonstrated that AA stimulated VCaP cell proliferation (Fig. 1A), which was consistent with previous observations in breast (24) and endometrial (25,26) cancer cell lines. Conversely, EPA effectively inhibited prostate cancer cell growth in vitro.…”

Omega-3 polyunsaturated fatty acids as an angelus custos to rescue patients from NSAID-induced gastroduodenal damage

“…Mammals cannot naturally produce n-3 PUFAs, and so must rely on a dietary supply-from fish, walnuts, olive oil, etc. Since fat-1 transgenic mice carry an abundance of n-3 PUFAs but low levels of n-6 PUFAs in their organs and tissues in the absence of dietary n-3 PUFAs, this resulted in significant benefits with regard to clinical diseases and these mice emerged as a new model for omega-3 research [24], as exemplified as follows: reduced carcinogenesis and cancer prevention [25][26][27] and protection from metabolic diseases [28,29], osteoarthritis [30], several ischemic injuries [31,32], nonalcoholic steatohepatitis [33,34], and oxidative injury [34]. Since Lim et al [35] showed inhibition of hepatocellular carcinoma growth through blocking of bcatenin and COX-2 and these anticancer effects shared the molecular mechanisms of NSAIDs, our group hypothesized that n-3 PUFAs might impose NSAID-sparing effects.…”

Elevation of ω-3 Polyunsaturated Fatty Acids Attenuates PTEN-deficiency Induced Endometrial Cancer Development through Regulation of COX-2 and PGE2 Production

“…Clinically, long-term high intake of diets or supplements enriched in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were associated with lower risk of endometrial cancer 16 17 . Dietary ω-3 PUFAs significantly attenuated endometrial cancer cell growth in xenograft models 18 . Therefore, high circulating and tissue contents of ω-3 PUFAs may be an important tool in the prevention and treatment of cancer pathogenesis 11 19 .…”